MULTI-ARM SINGLE MOLECULAR WEIGHT POLYETHYLENE GLYCOL, ACTIVE DERIVATIVE THEREOF, AND PREPARATION AND APPLICATION THEREOF

• US 20200131109A1
• Filed: 12/30/2019
• Published: 04/30/2020
• Est. Priority Date: 06/30/2017
• Status: Active Grant

• Current Assignee: Jenkem Technology Co., Ltd. (Tanjin)
• Original Assignee: Jenkem Technology Co., Ltd. (Tanjin)
• Inventors: WEI, ZHEN, LIN, MEINA, ZHAO, XUAN
• Granted Patent: US 11,518,728 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: C07C 235/08 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 31/202 Ethylene glycol
• CPC Class Codes: C07C 59/305 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07D 303/12 with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
• CPC Class Codes: C08G 65/3322 acyclic
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Being used for drug modification, the multi-arm single molecular weight polyethylene glycol and an active derivative thereof provided herein can effectively improve the solubility, stability, and immunogenicity of the drugs, improve the absorption of the drugs in vivo, prolong the half-life of the drugs, and increase bioavailability, enhance efficacy, and reduce toxic and side effects of the drugs. A gel formed from the active derivative of the multi-arm single molecular weight polyethylene glycol provided herein can be used for the preparation of controlled release drugs so as to prolong the action time of the drugs, thereby reducing the number of administrations and improving patient compliance.

Claims

1. A compound having the following structure:

A

X₁—

Y)_n 

 

(I)

wherein A is a core structure, and is a polyol group selected from the group consisting of;

residues of pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol, and glyceryl ether groups thereof,

X₁ is a linking group selected from any one or a combination of two or more of the group consisting of;

—

(CH₂)_i—

, —

(CH₂)_iO—

, —

(CH₂)_iNHCO—

, —

(CH₂)_iCONH—

, —

(CH₂)_iOCO—

, and —

(CH₂)_iCOO—

, and i is an integer from 1 to 10,

Y is a terminal group selected from any one of the group consisting of;

hydrogen, hydroxyl, carboxyl, ester group, ketone group, amino, mercapto group, maleimide group, alkynyl, and azido, and

n is an integer from 3 to 24.

2. The compound according to claim 1, wherein the A has the following structure:

3. The compound according to claim 1, wherein the A is selected from the following structures:

4. The compound according to claim 1, wherein the X₁ is selected from any one or a combination of two or more of the group consisting of:

—

CH₂—

, —

CH₂CH₂—

, —

CH₂CH₂CH₂—

, —

CH₂CONHCH₂—

, and —

CH₂CONHCH₂CH₂—

; and

/or,

in the Y, the ester group is selected from any one of the group consisting of;

5. The compound according to claim 1, wherein the compound is selected from the group consisting of:

11. A process for the preparation of a multi-arm single molecular weight polyethylene glycol according to claim 6, which comprises the step of reacting compound A

X₁—

Y)_n according to claim 1 with W—

X₂-PEG-PG to link them together, and the reaction formula is as follows;

A

X₁—

Y)_n+W-X₂-PEG-PG→

A

X₁—

R—

X₂-PEG-PG)_n

wherein W is a terminal group selected from any one of the group consisting of;

hydrogen, hydroxyl, carboxyl, ester group, ketone group, amino, mercapto group, maleimide group, alkynyl, and azido, and

PG is a hydroxyl protecting group;

preferably, the Y is carboxyl, and the W is amino;

or the Y is amino, and the W is carboxyl.

6. A multi-arm single molecular weight polyethylene glycol having the following structure:

A

X₁—

R—

X₂-PEG-H)_n 

 

(IV)

wherein A is a core structure, and is a polyol group selected from the group consisting of;

residues of pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol, and glyceryl ether groups thereof,

X₁ is a linking group selected from any one or a combination of two or more of the group consisting of;

—

(CH₂)_i—

, —

(CH₂)_iO—

, —

(CH₂)_iNHCO—

, —

(CH₂)_iCONH—

, —

(CH₂)_iOCO—

, and —

(CH₂)_iCOO—

, and i is an integer from 1 to 10,

R is a linking group selected from any one or a combination of two or more of the group consisting of;

—

NHCO—

, —

CONH—

, —

OCO—

, —

COO—

, —

O—

,

7. The multi-arm single molecular weight polyethylene glycol according to claim 6, wherein the A has the following structure:

8. The multi-arm single molecular weight polyethylene glycol according to claim 6, wherein the A is selected from the following structures:

9. The multi-arm single molecular weight polyethylene glycol according to claim 6, wherein the X₁ is selected from any one or a combination of two or more of the group consisting of:

—

CH₂—

, —

CH₂CH₂—

, —

CH₂CH₂CH₂—

, —

CH₂CONHCH₂— and

—

CH₂CONHCH₂CH₂—

; and

/or

the R is selected from any one or a combination of two or more of the group consisting of;

—

NHCO—

, —

CONH—

,

10. The multi-arm single molecular weight polyethylene glycol according to claim 9, wherein the multi-arm single molecular weight polyethylene glycol is selected from the following structures:

19. A conjugate of the multi-arm single molecular weight polyethylene glycol according to claim 7 or the active derivative thereof and a drug molecule.

20. A pharmaceutical composition comprising the conjugate of claim 19 and a pharmaceutically acceptable additive.

12. A multi-arm single molecular weight polyethylene glycol active derivative having the following structure:

A

X₁—

R—

X₂-PEG-F)_n 

 

(V)

wherein A is a core structure, and is a polyol group selected from the group consisting of;

residues of pentaerythritol, oligo-pentaerythritol, glycerol and oligoglycerol, and glyceryl ether groups thereof,

X₁ is a linking group selected from any one or a combination of two or more of the group consisting of;

—

(CH₂)_i—

, —

(CH₂)_iO—

, —

(CH₂)_iNHCO—

, —

(CH₂)_iCONH—

, —

(CH₂)_iOCO—

, and —

(CH₂)_iCOO—

, and i is an integer from 1 to 10,

R is a linking group selected from any one or a combination of two or more of the group consisting of;

—

NHCO—

, —

CONH—

, —

OCO—

, —

COO—

, —

O—

,

13. The active derivative according to claim 12, wherein the A has the following structure:

14. The active derivative according to claim 12, wherein the A is selected from the following structures:

15. The active derivative according to claim 12, wherein the X₁ is selected from any one or a combination of two or more of the group consisting of:

—

CH₂—

, —

CH₂CH₂—

, —

CH₂CH₂CH₂—

, —

CH₂CONHCH₂— and

—

CH₂CONHCH₂CH₂—

; and

/or

the R is selected from any one or a combination of two or more of the group consisting of;

—

NHCO—

, —

CONH—

,

16. The active derivative according to claim 12, wherein the multi-arm single molecular weight polyethylene glycol active derivative is selected from the following structures:

17. The active derivative according to claim 16, wherein in formula V-1, the m is 12 or 24, and the F_11-14 are all

18. A gel formed from the active derivative of claim 12.